Patients on mechanical ventilation need aerosolized therapy through an endotracheal tube and a ventilated circuit. In the critical care setting, patients received inhalation therapy in the form of wet aerosols via nebulizers or pressurized metered-dose inhalers (pMDI). However, an ineffective and inconsistent aerosol delivery due to drug loss in a ventilated system is a major problem for aerosolized therapy in these patients. Dry powder inhaler (DPI) has been a promising inhaler that has no ‘rain-out’ of wet aerosol on the circuit. This review will summarize the state of the art for aerosol delivery to mechanically ventilated patients with special emphasis on emerging opportunities for dry powder aerosols. Beside inhaler itself, drug delivery to mechanically ventilated patients depends on the ventilator circuit-related factors such as the pattern of inspiration, the volume of inhalation and the volumetric flow rate. Patients on mechanical ventilation differ from patients who can breathe by themselves (unassisted spontaneous breathing) or patient who receive direct-to-mouth inhalation. Drug delivery during mechanical ventilation is affected by the factors that directly related to ventilator circuit that controls a patient’s breathing. Thus, these ventilator circuit-related factors that play an important role in drug delivery efficiency will be discussed in this review.